The incidence of tangled masses of paired helical filaments in neurons and amyloid plaques in intercellular regions of the temporal lobe in brain are the neuropathological findings used to confirm the clinical diagnosis of Alzheimer disease (AD), the most common cause of dementia in the elderly US population. The invariable presence of activated astrocytes and microglia in close proximity to, surrounding, and within the brain lesions is a largely ignored feature of the neuropathology of AD, and other neurodegenerative disorders associated with dementia. Preliminary data presented here suggests that glia, via factors that they synthesize and release, contribute to the neuropathological features of AD. We will concentrate on a particular astrocyte-derived factor, S100beta, a calcium binding, neurotrophic protein encoded by a gene on chromosome 21. Chromosome 21 gene products and their actions appear to be of particular importance in AD since the genes encoding S100beta, beta-amyloid precursor protein, and a marker for familial AD are located on this chromosome. An extra copy of all or part of chromosome 21 results in Down syndrome (DS, trisomy 21) which is the most common cause of congenital mental retardation in the US (1 per 800 live births). Interestingly, Down syndrome culminates at middle age in AD-like dementia and neuropathology, including glial reactivity. We hypothesize that alterations in genetic expression of glial-derived regulators, particularly S100beta, contribute to glial reactivity, neuronal pathologies, and to the pattern of calcium deposits in AD brain. Using Western and Northern analyses, immunohistochemistry, and in situ hybridization, we propose to determine the levels of S100beta and its encoding mRNA in specific cell types and regions in AD brain as well as the levels of other molecules that may influence the expression of S100beta or be influenced by an increase in S100beta expression. Successful completion of the aims of this proposal could provide information about relationships that may form a link between the pathological features of glia, neurons, and extracellular mineral deposits in an age-related disorder, AD.